3-Hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinane (additional name: 4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxy-2-phenyl-1,2-oxaphosphinane 2-oxide) is referred to as “Compound I” in the present invention. Compound I is a compound (also called 3.48 or 3.1 in previous documents) that has been proven to be an efficient anti-cancer agent and in particular for reducing or preventing the appearance of metastases, as described by the PCT applications WO2009/004096 and WO2014/128429, respectively. Compound I and its use against glioblastoma is more specifically disclosed in J. Med. Chem. 2012, 55, 2196-2211. The example of method provided in this document to synthesise compound I allows its formation in a four diastereoisomers mixture, arising from the creation of two chiral centers. From the four formed enantiopure diastereoisomers, the most potent diastereoisomer is PST3.1a.
As disclosed in the cited prior art, synthesis of PST3.1a (also referred herein as compound of formula (I)) can be performed by reacting 2,3,5-tri-O-benzylarabinose 3 and ethyl phenylphosphinate 4 as shown in Scheme 1 below.

Treatment of an equimolar of 3 and 4 in THF (Tetrahydrofuran) followed by addition of potassium tert-butoxide actually provides a mixture of 4 diastereoisomers in about equimolar amount. The 4 diastereoisomers mixture is called in the present description “mixture A” and the diastereoisomers comprised therein are represented below (Scheme 2).

After stirring of the obtained mixture (mixture A) and evaporation of the solvent, chloroform was added and the obtained organic solution was washed with ammonium chloride, dried, filtered, and the solvent evaporated to obtain a yellow oil residue containing the four diastereoisomers. After purification on silica gel chromatography, separation of the four diastereoisomers by chromatography on preparative reverse-phase HPLC can be performed. However, the global yield of PST3.1a is low (about 4%). Other chromatography or fractional crystallization-based methods have been performed in an attempt to increase the overall yield of PST3.1a. However, technical specifications, solvents and/or purification techniques involved in these methods do not allow it to be efficiently and easily converted into an industrial scale.
A permanent aim in organic synthesis is to create synthesis processes that can be transposed into industrial conditions. In order to meet requirements for industrial processes, different parameters of the synthesis are to be optimized. First, solvents must be as little volatile as possible, in order to be easily recoverable. Thus, chlorinated volatile solvents, e.g. dichloromethane, chloroform and/or carbon tetrachloride, are preferably avoided. In addition, the numbers of equivalents of reagents required are preferably limited, the temperatures involved preferably remain in an easily accessible range, and easy to proceed purification steps should be privileged. Finally, reaction mixtures and isolated product are preferably thermally stable.
Current Good Manufacturing Practice (c-GMP) has been defined for preparation of drug products for administration to humans or animals. GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mixups, and errors. GMP regulations address issues including recordkeeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling.
To the Applicant knowledge, no industrially applicable process to synthesise compound PST3.1a has been described so far.
Hence, an object of the present invention is to provide a process for preparing PST3.1a that can be adapted easily and efficiently to industrial scale, as compared to the process of the prior-art wherein unsafe compounds, such as chloroform and diethyl ether, and/or column chromatography are used.
Moreover, since a highly pure form, typically greater than 99.0 percent, of any drug is generally required for human treatment, a method that combines the control of the formation of isomers and a readily final purification is particularly advantageous.
Furthermore, in addition to the method issues, it is the aim of the invention to provide solid state physical properties of Compound I. These properties can be influenced by controlling the conditions under which Compound I is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to a thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x-ray crystallography and infrared spectrometry.
Generally, the crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. It can also exhibit lower hygroscopicity, improved bulk properties, and/or flowability.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. There is a need in the art for crystalline Compound I and advantageous polymorphic forms thereof.